: Pituitary adrenocorticotropic hormone (ACTH) is a major stimulus for glucocorticoid synthesis, and is derived from processing of pro-opiomelanocortin. Dr. Drouin has been working for many years to understand transcriptional control of the POMC gene, and especially the mechanisms of negative feedback exerted by glucocorticoids on POMC. He has characterized two pathways which may mediate glucocorticoid effects on this gene. One involves binding of the glucocorticoid receptor (GR) to a negative glucocorticoid-response element in the gene and the formation of novel receptor:DNA complexes. The other involves target DNA sequences which do not bind GR and thus, must utilize different mechanisms. The proposed research will define the molecular mechanisms responsible for repression through each pathway using POMC- expressing tumor cells, AtT-20 cells. Genetic analysis of promoter sequences and biochemical analysis of in vitro interactions will be used to define these mechanisms at the molecular level. The role of each pathways in vivo will be assessed in transgenic mice. The novel features of glucocorticoid receptor interaction with POMC DNA, and of the dual mechanisms for glucocorticoid repression, indicate that the POMC gene is an excellent paradigm for the understanding of nuclear receptor- dependent repression of transcription.